Mesenchymal stem cells (MSCs) have been gaining increasing promise as a biotherapy that can suppress disease in murine SLE models and in an initial trial of SLE patients. Major limitations of efficacy in the human trial, however, were that their beneficial effects (SLEDAI scores and proteinuria) were partial and were short lived. While MSCs exert their immunosuppressive effects in large part via the induction of Foxp3+ T regulatory cells (iTregs), the relationship of their immunosuppression to that of Treg immunosuppression has not been clarified. Moreover, how to prolong MSC immunosuppression and sustain the Tregs they produce long term remains unknown. Our recent work found that a previously unrecognized event in Th1 and Th17 cell activation is that dendritic cell (DC)-CD4+ cell partners endogenously produce C3a and C5a and up-regulate their surface expression of C3a and C5a receptors (C3aR/C5aR) G protein coupled receptors (GPCRs). The local C3a and C5a ligate up- regulated C3aR and C5aR on the interacting DC-CD4+ cell partners. We found that this GPCR signaling provides not only costimulatory but also survival signals that are integral to Th1 and Th17 cell responses. Importantly, our recently published work showed that the absent C3aR/C5aR signaling into nave CD4+ cells enables auto-inductive TGF- signaling which represses CD4+ cell CD40L up-regulation and IL-6 production and leads to the generation of Tregs. An important clinical outcome of these findings was that in contrast difficulties in the past in generating human Tregs that exert robust suppressor activity and are stable, our findings now provide a route to achieve this. Centrally relevant to SLE, our preliminary studies now show that absent C3aR/C5aR signaling in B cells, abolishes CD40 up-regulation and IL-6 production, reduces Ab production and class switching recombination (CSR), and suppresses TLR signaling. Consistent with this, we have found that disrupting C3aR/C5aR signaling virtually abolishes disease in the pristane induced murine SLE model. MSCs, like CD4+ cells and DCs, express C3aR/C5aR. In unpublished work, we have found that disrupting C3aR/C5aR signaling into Tregs sustains Treg stability in vivo for >7 months. We additionally have developed methods to precisely quantify the effects of disrupted C3aR/C5aR signaling on MSC stability and to assess the interaction of MSCs with Tregs in vivo. The centerpiece of this proposal is that it is a collaboration between our lab and that of Arnold Caplan, a pioneer in MSC biology. The Aims are directed at optimally harnessing MSC and Treg immunosuppression for controlling SLE. The unique collaboration will be conducted with murine SLE models exploiting our novel mouse strains and with SLE patients exploiting our new insights on human Treg lineage commitment.